Human Reproduction, Vol. 16, No. 3, 510-512,
March 2001
© 2001 European Society of Human Reproduction and Embryology
Internal jugular vein thrombosis after ovarian stimulation: Case report
1 Department of Gynecology-Fertility, and 2 Department of Gastroenterology, C.A.Z.K.Groeninghe Campus Sint-Niklaas,Houtmarkt 33, Kortrijk, Belgium
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Abstract |
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Thromboembolic events are serious, but fortunately rare, complications following ovarian stimulation for IVF. Here, we report a case of internal jugular vein thrombosis after ovarian stimulation with gonadotrophins. Most of the cases of thrombosis are late complications of ovarian hyperstimulation syndrome (OHSS) or hereditary hypercoagulability. Screening for these risk factors in our patient was negative. The patient was succesfully treated with low molecular weight heparin and a twin pregnancy is ongoing.
Key words: jugular vein/thrombosis/ovulation induction
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Introduction |
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Most cases of thrombosis after ovarian stimulation with gonadotrophins are a complication of ovarian hyperstimulation syndrome (OHSS). A hypercoagulable state is created due to haemoconcentration as a result of the escape of intravascular fluid into the third space. There is a rise in blood viscosity and the coagulation factors become concentrated (Kodama et al., 1996
). A hereditary hypercoagulable state is also a risk factor for thrombosis, e.g. antiprotein C (APC) resistance (Hollemaert et al., 1996; Horstkamp et al., 1996), antithrombin III deficiency (Kligman et al., 1995), and protein C and S deficiency. Our patient was screened for haemoconcentration and hereditary hypercoagulability, and both were negative. The only risk factors present were stimulation with gonadotrophins and an ongoing twin pregnancy. |
Case report |
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TopAbstractIntroductionCase reportDiscussionConclusionsReferences |
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The patient was a 31 year old woman with a 3 year history of secondary infertility due to ovulatory dysfunction and endometriosis who had underone IVF and embryo transfer after ovarian stimulation with gonadotrophins. She first became pregnant in 1994 after taking clomiphene citrate. Several further attempts to achieve pregnancy were made using clomiphene citrate and intra-uterine insemination, but with no success.
In October 1999, she began a long schedule for IVF and intracytoplasmic sperm injection (ICSI). She started with buserelin puffs (Suprefact; Aventis, Brussels, Belgium) and on the fourth day of the next cycle, ovarian stimulation was initiated with gonadotrophins (Humegon; Organon; Brussels, Belgium; two ampoules/day). After 12 days of stimulation, the patient developed 11 follicles with a diameter of 15–22 mm. The concentration of oestradiol was 2069 pg/ml.
Follicle aspiration was carried out 36 h after administration of 10 000 IU of human chorionic gonadotrophin (HCG) and eight oocytes were recovered. Six of these oocytes were used for ICSI and five were fertilized. Two embryos were transferred 3 days later and the patient received 1500 IU of HCG every 3 days for luteal phase support. At 11 days after embryo transfer, the patient presented with mild abdominal distension due to enlarged ovaries (86x60 and 60x80 mm) and a small amount of ascites.
A blood sample showed an oestradiol concentration of 1107 pg/ml, and a progesterone concentration of >60 000 ng/ml, HCG = 102 IU/l, haemoglobin = 13.1 g/dl; haematocrit = 40%; Na = 132 mmol/l; and total albumin = 56 g/l.
HCG (Pregnyl) was stopped and progestagens (Utrogestan; Piette, Drogenbos, Belgium) 3x2 compr./day vaginally were continued, because of a risk for OHSS. HCG concentrations rose quickly, reaching 9413 IU/l after 12 days. One month after embryo transfer, the patient presented with neck swelling and pain. Echography and Doppler ultrasound demonstrated an occlusive thrombus involving the left internal jugular vein. Echography from the uterus showed a twin pregnancy, di-amniotic with positive heart activity and this twin pregancy is still ongoing. Both ovaries were polycystic and enlarged (8x5 and 6x5 cm). See Table I for follow-up blood results. There was no evidence of haemoconcentration.
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Full anticoagulation with 0.6 ml low molecular weight heparin (Fraxiparine; Sanofi, Brussels, Belgium) s.c. twice a day was initiated for 3 weeks. During the whole pregnancy, the patient will receive 0.6 cc Fraxiparine s.c. per day until 3 weeks post-partum, discontinued for the birth. Screening for a hypercoagulability due to antithrombin III, protein C or protein S deficiency, APC resistance (factor V Leiden) and lupus anticoagulans were all negative.
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Discussion |
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TopAbstractIntroductionCase reportDiscussionConclusionsReferences |
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A review of literature indicates that thromboembolic events after ovarian stimulation are usually associated with OHSS (Benilfa et al., 1994
). Increased capillary permeability gives hypovolaemia due to escape of fluid to the extravascular compartment (Fournet et al., 1991) (see Figure 1). The increased capillary permeability is due to increased angiogenesis. Angiogenesis can be induced by the renin–angiotensin cascade, cytokines, histamines, prostaglandins and vascular endothelial growth factors.
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Haemoconcentration and activation of the coagulation cascade, rise of thrombin–antithrombin III, and plasmin–antiplasmin complexes, and a rise in platelet levels is seen in patients with OHSS (Kodama et al., 1996
). In patients with severe OHSS, consideration should be given to treatment with low dose heparin. However, despite this prophylaxis, a case of internal jugular vein thrombosis has been reported (Hignett et al., 1995). Prevention of OHSS is important to reduce the risk of thrombosis. Risk factors are young, thin women with polycystic ovarian syndrome (PCOS), a rapid increase in oestradiol concentration during stimulation (>3500 pg/ml), multifollicular growth (>15 immature follicles) and the use of GnRH agonists.
Preventive measures include: (i) no HCG for ovulation induction or for luteal phase support in the group at risk; (ii) stimulation using a low dose of gonadotrophins for a longer period; (iii) early timed follicular aspiration; and (iv) i.v. albumin therapy at the time of follicular aspiration (Delbeke et al., 1998). Despite prophylactic albumin therapy, cases of severe OHSS and thrombosis have been reported (Moutos et al., 1997).
The increased risk of thrombosis during ovarian stimulation without OHSS (as in our case), is due to endogenous hyper-oestrogenism. The multifollicular growth in the ovaries with a high oestradiol concentration is responsible for an increased rate of thrombosis. Here, the thrombosis occurred several weeks after resolution of a mild degree of hyperstimulation. The activation of coagulation can thus persist several weeks after resolution of symptoms.
Another risk for thrombosis is a hereditary hypercoagulable state. APC resistance or factor V Leiden mutation was reported in a case of jugular vein thrombosis after ovarian hyperstimulation (Horstkamp et al., 1996). A 3–5% frequency of this thrombophilic disorder has been found in the Dutch population (Koster et al., 1993). This risk is 10-fold higher than the risk for ATIII, protein C and S deficiencies. Cases of internal jugular vein thrombosis and these thrombophilic disorders were also described (Kligman et al., 1995). An unusually located venous thrombosis should prompt an evaluation of a hypercoagulable state; in our patient, the screening was negative.
Pregnancy and ovarian hyperstimulation creates a hypercoagulable state (Ellis et al., 1998); a twin pregnancy is ongoing in our patient. Additional risk factors for internal jugular vein thrombosis are iatrogenic thrombosis after venous catherisation, i.v. drug abuse, tumour compression and paraneoplastic phenomena. Here, we can rule out such factors.
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Conclusions |
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TopAbstractIntroductionCase reportDiscussionConclusionsReferences |
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OHSS is a high risk factor for thromboembolic events. In all cases of severe OHSS, prophylactic minidoses of heparin schould be given. Prevention of OHSS as described above can reduce the risk of thrombosis. In all patients with a history of thromboembolic events or known hereditary hypercoagulability, prevention with minidoses of heparin during IVF can be useful.
Low molecular weight heparins have been used succesfully in pregnancy and are particularly suited for use in this setting because they do not cross the placenta, appear to cause less osteoporosis during long-term use than standard heparin, and do not require routine laboratory monitoring.
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Acknowledgments |
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The authors thank Rosie Noppe of our department for her technical assistance and layout of manuscript.
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Notes |
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3 To whom correspondence should be addressed.
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References |
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TopAbstractIntroductionCase reportDiscussionConclusionsReferences |
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Benilfa, J.L., Conard, J., Naouri, M. et al. (1994) Syndrome d'hyperstimulation, ovarienne et thrombose. A propos d'un cas de thrombose de la veine jugulaire interne. Revue de la literature. Gynecol. Obstet. Biol. Reprod., 23, 778–783.
Delbeke, L., De Neubourg, D. and De Loecker, P. (1998) Het ovarieel hyperstimulatiesyndroom. Nieuwe inzichten en therapeutisch beleid. Tijd. Geneesk., 54, 1463–1472.
Ellis, M.H., Nun, I.B., Ven, A.B. et al. (1998) Internal jugular vein thrombosis in patients with ovarian hyperstimulation syndrome. Fertil. Steril., 69, 140–142.[Web of Science][Medline]
Fournet, N., Surrey, E. and Kerin, J. (1991) Internal jugular vein thrombosis after ovulation induction with gonadotrophins. Fertil Steril., 56, 354–357.[Web of Science][Medline]
Hignett, M., Spence, J.E.H. and Claman, P. (1995) Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation syndrome despite mini-dose heparin prophylaxis. Hum. Reprod., 10, 3121–3123.
Hollemaert, S., Wautrecht, J.C., Capel, P. et al. (1996) Thrombosis associated with ovarian hyperstimulation syndrome in a carrier of the factor V Leiden mutation. Thromb. Haemost., 76, 275–277.
Horstkamp, B., Lubke, M., Kentenich, H. et al. (1996) Internal jugular vein thrombosis caused by resistance to activated protein C as a complication of ovarian hyperstimulation after in vitro fertilization. Hum. Reprod., 11, 280–282.
Kligman, I., Noyes, N., Benadiva, C.A. and Rosenwaks, Z. (1995) Massive deep vein thrombosis in a patient with AT III deficiency undergoing ovarian stimulation for IVF. Fertil. Steril., 63, 673–676.[Web of Science][Medline]
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Submitted on April 5, 2000; accepted on December 7, 2000.
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